CN1210529A - Dihydrobenzofuran and related compounds useful as anti-inflammatory agents - Google Patents
Dihydrobenzofuran and related compounds useful as anti-inflammatory agents Download PDFInfo
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- CN1210529A CN1210529A CN97191977A CN97191977A CN1210529A CN 1210529 A CN1210529 A CN 1210529A CN 97191977 A CN97191977 A CN 97191977A CN 97191977 A CN97191977 A CN 97191977A CN 1210529 A CN1210529 A CN 1210529A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
Abstract
A compound having structure (I) wherein (a) n is from 1 to about 3; (b) X is selected from the group consisting of O, S, SO, or SO2; (c) Y is independently hydrogen or straight, branched or cyclic alkyl having from 1 to about 4 carbon atoms, or the Y's are bonded together to form an alkanyl ring having from 3 to about 7 atoms; (d) Z is hydrogen or straight, branched or cyclic alkyl having from 3 to about 10 atoms other than hydrogen; (e) W is O or S; and (f) R1, R2 and R3 are independently hydrogen, straight, branched or cyclic alkyl having from 1 to 10 carbon atoms, aryl, heterocyclyl, heteroaryl, hydroxy, or alkoxy; or R1, R2 or R3 may be bonded to form one or more rings each ring having from 3 to about 7 atoms wherein from 1 to 3 atoms may be heteroatoms. Pharmaceutical compositions comprising such compounds, and methods of treating inflammation or pain using such compounds.
Description
Technical field
The present invention relates to the on-steroidal anti-inflammatory agent, relate to the Dihydrobenzofuranes and the related compound of replacement particularly.
Background of invention
Have now found that some Dihydrobenzofuranes compound reaches the activity that has important change disease with other compound of its structurally associated.These compounds, Preparation Method And The Use are disclosed in the following document: authorized the U.S. Patent No. 4,670,457 of Doria, Romeo and Como on June 2nd, 1987; Authorized the United States Patent (USP) NO 4,849,428 of Dobson, Loomans, Mattews and Miller on July 18th, 1989; The patent of Yoshitomi Pharm.Ind.KK company is disclosed in the Japanese Patent publication No.53-005178 on January 1st, 1978; Hammond, M.L., I.E.Kopka, R.A.Zambias, C.G.Caldwell, J.Boger, F.Baker, T.Bach, " as 2 of the anti-oxidant formulation inhibitor of leukotriene biosynthesizing, 3-dihydro-5-cumarone alcohol " (2 of S.Luell and D.E.Maclntyre, 3-Dihydro-5-benzofuranols asAntioxidant-based Inhibitors of Leukotriene Biosynthesis), " journal of medicinal chemistry " (J.Med.Chem.), Vol.32 (1989), pp.1006-1020; Ortiz de Montellano, P.R. and M.A.Correia, " the suicide destruction of cytochrome P-450 in the oxidation drug metabolism " (Suicidal Destruction ofCytochrome P-450 During Oxidative Drug Metabolism), Ann.Rev.Pharmacol.Toxicol., Vol.23 (1983), pp.481-503; Chakrabarti; J.K., R.J.Eggleton, P.T.Gallagher; J.Harvey; T.A.Hicks, E.A.Kitchen, and C.W.Smith; " as 5-acyl group-3-replacement-cumarone-2 (the 3H)-ketone compounds of potential anti-inflammatory agent " (5-Acyl-3-substituted-benzofuran-2 (3H)-ones asPotential Anti-inflammatory Agents); " journal of medicinal chemistry " (J.Med.Chem.), Vol.30 (1987), pp.1663-1668.
An object of the present invention is to provide have effective antiinflammatory, the compound of pain relieving and/or antioxidant activity.
Another object of the present invention provides this less compounds of adverse side effect.
Another purpose of the present invention provides the method with these compounds for treating inflammation and/or pain.
Summary of the invention
The structure of The compounds of this invention is as follows:
In the formula,
(a) n is 1-3;
(b) X is selected from: O, S, SO or SO
2
(c) Y is hydrogen independently of one another, or the straight-chain alkyl of 1-4 carbon atom, branched hydrocarbyl or cyclic hydrocarbon radical, and perhaps Y is together with each other and forms the alkane ring (alkanyl ring) of 3-7 atom;
(d) Z is a hydrogen, or the straight-chain alkyl of 3-10 non-hydrogen atom, branched hydrocarbyl or cyclic hydrocarbon radical;
(e) W is O or S; And
(f) R
1, R
2And R
3Be hydrogen independently of one another, the straight-chain alkyl of 1-10 carbon atom, branched hydrocarbyl or cyclic hydrocarbon radical, aryl, heterocyclic radical, heteroaryl, hydroxyl or alkoxyl group; Perhaps R
1, R
2And R
3Can mutually combine forms one or more rings, and each ring has 3-7 atom and 1-3 atom wherein arranged can be heteroatoms.
Detailed Description Of The Invention
As used herein, unless indicate in addition, " alkyl " or " alkyl (alkanyl) " refers to straight chain, side chain or the cyclic hydrocarbon chain of saturated or undersaturated, replacement or non-replacement.Preferably, alkyl is C
1-C
10More preferably be C
1-C
8The spy is C goodly
1-C
4Preferred alkyl is a straight chain.Preferred branched hydrocarbyl has one or two side chain, and a side chain is more preferably arranged.Preferred cyclic hydrocarbon radical is monocyclic, or has the straight chain of monocycle end.Preferred alkyl is saturated.One or more pairs of keys are arranged unsaturated alkyl or/and one or more triple bond.Preferred unsaturated alkyl has one or two pair key and/or a triple bond, more preferably has a two key.Preferred alkyl is unsubstituted.Preferred substituted hydrocarbon radical is single replacement, two replacements or trisubstituted, more preferably is mono-substituted.Preferred hydrocarbyl substituent comprises: halogen atom, hydroxyl, oxo, alkoxyl group is (as methoxyl group, oxyethyl group, propoxy-, butoxy, pentyloxy), aryloxy is (as phenoxy group, chlorophenoxy, tolyloxy, the methoxyl group phenoxy group, the benzyloxy phenoxy group, the alkoxy carbonyl phenoxy group, the acyloxy phenoxy group), acyloxy is (as propionyloxy, benzoyloxy, acetoxyl group), carbamyl oxygen base, carboxyl, sulfydryl, alkylthio, the acyl sulfenyl, arylthio is (as thiophenyl, the chlorobenzene sulfenyl, alkyl sulfur-base, the alkoxy benzene sulfenyl, benzylthio-, the alkoxy carbonyl thiophenyl), aryl is (as phenyl, tolyl, alkoxyl phenyl, alkoxycarbonylphenyl, halogenophenyl), heterocyclic radical, heteroaryl, amino (as amino, one or two-C
1-C
3Alkyl amino, aminomethyl phenyl amino, methyl-benzyl amino), C
1-C
3Alkyl amido, urea groups, N ＇-alkyl urea groups, N ＇, N ＇-dialkyl group urea groups, N ＇, N ＇, N-trialkyl urea groups, guanidine radicals, N ＇-alkyl guanidine radicals, N ＇, N " dialkyl group guanidine radicals or alkoxy carbonyl.
As used herein, " alkoxyl group " refers to-the O-alkyl.
As used herein, " aryl " refers to have the part of the aromatic ring that does not replace or replace of 6-10 carbon atom.Preferred aryl groups is phenyl and naphthyl; Most preferred aryl is a phenyl.Preferred aryl groups is unsubstituted.Preferred substituted aryl is single replacement, two replacements or trisubstituted, more preferably is mono-substituted.The preferred aryl groups substituting group comprises: hydroxyl, sulfydryl, halogen atom, methyl, ethyl and propyl group.
As used herein, " heterocyclic radical " refer to have 3-8 annular atoms the satisfying and/or undersaturated non-aromatic ring of (comprising about 2-6 carbon atom and about 1-4 heteroatoms that is selected from O, S and N).Preferred heterocycle is saturated.Preferred heterocycle has 5-6 atom in ring, comprise 1 or 2 heteroatoms in the ring, and 1 heteroatoms is more preferably arranged in ring.Concrete preferred heterocycle comprises: piperidyl, tetrahydro-thienyl, pyrrolidyl, piperazinyl, morpholinyl, thio-morpholinyl, THP trtrahydropyranyl, tetrahydrochysene sulfo-pyranyl, tetrahydrofuran base, imidazolidyl, pyrazolidyl, oxazolidinyl, isoxazole alkyl, thiazolidyl, isothiazole alkyl, azepines base, oxepin base (oxepinyl), thiepin base (thiepinyl), triazolidinge, tetrazolium alkyl.Heterocycle can be unsubstituted or replace, be preferably unsubstituted.Preferred substituted heterocycle is single replacement, two replacements or trisubstituted, more preferably is mono-substituted.Preferred heterocyclic substituting group comprises: alkyl, halogen atom, hydroxyl, alkoxyl group, acyloxy, carboxyl, carbamyl oxygen base, sulfo-, amino, amido, urea groups, guanidine radicals, sulfo-guanidine radicals (thiocarbamamido), sulfo-urea groups.
As used herein, " heteroaryl " refers to the aromatic ring of 5 or 6 atoms, and 1-5 carbon atom and 1-4 heteroatoms that is selected from O, S and N wherein arranged.Preferred heteroaryl has 1-3 heteroatoms in ring, 1 or 2 heteroatoms is more preferably arranged in ring.Concrete preferred heterocycle comprises: furyl, thienyl, replaced by alkyl on the nitrogen or unsubstituted pyrryl, thiazolyl, oxazolyl, replaced by alkyl on the nitrogen or unsubstituted 5-imidazolyl, isoxazolyl, isothiazolyl, replaced by alkyl on nitrogen or unsubstituted pyrazolyl, oxadiazole base, thiadiazolyl group, triazolyl, tetrazyl, pyridyl, pyrimidyl, pyrazinyl.The heteroaryl of condensed ring comprises: Imidazothiazole quinoline base (imidazothiazolinyl), imidazopyridyl, imidazo imidazolinyl, indyl, quinolyl, isoquinolyl.Heteroaryl can be unsubstituted or replace, be preferably unsubstituted.Preferred substituted heteroaryl is single replacement, two replacements or trisubstituted, more preferably is mono-substituted.The substituting group of preferred heteroaryl comprises: alkyl, halogen atom, hydroxyl, alkoxyl group, sulfo-, nitro, amino, nitro, amido, urea groups, guanidine radicals, sulfo-guanidine radicals, sulfo-urea groups.
As used herein, " halogen atom " refers to fluorine, chlorine, bromine, iodine.Preferred halogen atom is fluorine, chlorine, bromine, is preferably chlorine and bromine, more preferably is chlorine.
Compound
The present invention includes compound with following structure:
In the formula,
(a) n is 1-3;
(b) X is selected from: O, S, SO or SO
2
(c) Y is hydrogen independently of one another, or the straight-chain alkyl of 1-4 carbon atom, branched hydrocarbyl or cyclic hydrocarbon radical, and perhaps Y is together with each other and forms the alkane ring (alkanyl ring) of 3-7 non-hydrogen atom;
(d) Z is a hydrogen, or the straight-chain alkyl of 3-10 non-hydrogen atom, branched hydrocarbyl or cyclic hydrocarbon radical;
(e) W is O or S; And
(f) R
1, R
2And R
3Be hydrogen independently of one another, the straight-chain alkyl of 1-10 carbon atom, branched hydrocarbyl or cyclic hydrocarbon radical, aryl, heterocyclic radical, heteroaryl, hydroxyl or alkoxyl group; Perhaps R
1, R
2And R
3Can mutually combine forms one or more rings, and each ring has 3-7 atom and 1-3 atom wherein arranged can be heteroatoms.
In said structure, each Y is selected from respectively: hydrogen, 1 cyclic hydrocarbon radical (as cyclopropyl) to the unsaturated straight or branched alkyl and 3 carbon atoms of having an appointment of about 4 carbon atoms is arranged, perhaps Y is joined together to form the 3 alkane rings to about 7 carbon atoms in the ring.Each Y is preferably hydrogen, methyl, ethyl or cyclopropyl; More preferably be hydrogen or methyl; Be methyl best.Two Y are suitable identical.When Y was joined together to form ring, ring was preferably cyclopropyl, cyclobutyl or cyclopentyl, more preferably cyclopropyl.
In said structure, Z is selected from: undersaturated branched hydrocarbyl or cyclic hydrocarbon radical, and do not replace or phenyl that alkyl replaces, or benzyl, Z has 3 to about 10 non-hydrogen atoms.Z is preferably saturated.
Z is preferably the branched alkane alkyl of 3 to 10 carbon atoms of having an appointment, 4 to 6 carbon atoms of preferably having an appointment.Z is preferably the branched alkane alkyl of 2 or a plurality of side chains, has 2 side chains better.Preferable branched alkane alkyl Z comprises: the tertiary butyl, neo-pentyl, sec.-propyl; Best is the tertiary butyl.Preferable cycloalkyl group Z comprises: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl.Same preferred cycloalkyl group Z comprises: end has the methyl or the ethyl of cyclopropyl, cyclobutyl or cyclopentyl, especially cyclopropyl methyl or cyclopropyl ethyl.Preferred Z also has unsubstituted phenyl or benzyl.
In said structure, R
1, R
2And R
3Be respectively hydrogen, or the straight-chain alkyl of 1-10 carbon atom, branched hydrocarbyl or cyclic hydrocarbon radical.R
1And R
2And/or R
3Can mutually combine forms the alkane ring, and have an appointment in the ring 3-7 the carbon atom and the 1-3 that wherein has an appointment can be the heteroatomss that is selected from O, N or S.Other preferred R bases comprise: aryl, heterocyclic radical, heteroaryl, hydroxyl or alkoxyl group.
Preferable compound is included in down in the tabulation among the present invention:
Compound number R
3
1 methyl
2 ethyls
3 propyl group
In order to measure and estimate pharmacological activity, test The compounds of this invention activity in animal body with the known measuring method of various these those skilled in the art.Adopt design to be used for testing the measuring method of The compounds of this invention antagonism local edema (feature of inflammatory reaction), just can prove the anti-inflammatory activity of The compounds of this invention easily.This known test example comprises that rat carrageenan causes that swollen examination is tested, the test of azolactone inductive mouse ear inflammation and the test of eicosatetraenoic acid (arachadonic acid) inductive mouse ear inflammation.Analgesic activities can record in the known model in this field, tests and rat Randall ﹠amp as the mouse writhing that the phenyl benzoquinoline causes; The Selitto test.Known another useful testing method is rat assist agent arthritis test in this field, and it is at chronic model but not estimates a kind of useful model of anti-inflammatory activity, arthritis and anti-assimilating activity in the acute model.
The test method that these and other of pharmacological activity is suitable is disclosed in and/or is incorporated in U.S. Patent No. 4,130,666 (Moore, on December 19th, 1978 authorized); U.S. Patent No. 4,431,656 (people such as Katsumi, on February 14th, 1984 authorized); U.S. Patent No. 4,440,784 (people such as Katsumi, on April 3rd, 1984 authorized); Japanese patent application 85/54315 (people such as Katsumi, on March 28th, 1985 is open); European Patent Application No. No.0,059,090 (Yamanuchi Pharmaceutical Company Ltd., September 1 nineteen eighty-two is open); Opas, E.V., R.J.Bonney ﹠amp; J.L.Humes is at " eicosatetraenoic acid causes the synthetic of Prostaglandins and Leukotrienes in the scorching mouse ear " (" the Prostaglandin and Leukotriene Synthesis in Mouse Ears Inflamed by ArachadonicAcid " of " dermatological studies magazine " 84 volume the 4th phase 253-256 page or leaf, The Journal of Investigative Dermatology, Vol.84, No.4 (1985), pp.253-256); Swingle, K.F., R.L.Bell ﹠amp; G.G.I.Moore rolls up " anti-inflammatory activity of antioxidant " (" Anti-inflammatory Activity ofAntioxidants " in the 4th chapter 105-126 page or leaf in " anti-inflammatory and antirheumatic thing " III, Anti-inflammatory and Antirheumatic Drugs, Vol. III, Chapter 4, K.D.Rainsford, ed., CRC Press, Inc., (1985), pp.105-126); Adamkiewicz, V.W., W.B.Rice ﹠amp; J.D.McColl " antiinflammation of trypsinase on normal and adrenoprival rat " (" Antiphlogistic Effect ofTrypsin in Normal and in Adrenalectomized Rats ", Canadian Journal of Biochemistry﹠amp in " Canadian biological chemistry and physiology magazine " the 33rd volume 332-339 page or leaf; Physiology, Vol.33 (1955), pp.332-339); Sellye, H. " participating in the pathogenetic further research of sacroiliitis " (" the FurtherStudies Concerning the Participation of the Adrenal Cortex in the Pathogenesis ofArthtitis " in " BMJ " the 2nd volume 1129-1135 page or leaf about adrenal cortex, British Medical Journal, Vol.2 (1949), PP.1129-1135); And Winter, C.A., E.A.Risley ﹠amp; G.W.Nuss is at " carrageenin causes the anti-inflammatory drug measuring method of rat hindleg oedema " (" Carrageenan-Induced Edema inHind Paw of the Rats as an Assay for Antiinflammatory Drugs " of " experimental biology and medical association's meeting will " the 111st volume 544-547 page or leaf, Proceedings ofSociety of Experimental Biology and Medicine, Vol.111 (1962), pp.544-547); Otterness, I. ， ﹠amp; " laboratory method of test nonsteroidal anti-inflammatory drugs " (" the Laboratory Methods for Testing NonsteroidalAntiinflammatory Drugs " of M.L.Bliven in " nonsteroidal and-inflammatory drug " the 3rd chapter 111-252 page or leaf, Nonsteroidal Antiinflammatory Drugs, Chapter 3, J.G.Lombardino, ed., John Wiley ﹠amp; Sons, Inc. (1985), pp.111-252); Hitchens, J.T., S.Goldstein, L.Shemano ﹠amp; J.M.Beiler is at " analgesic activity of stimulator on three kinds of experimental pain models " (" Analgesic Effects ofIrritants in Three Models of Experimentally-Induced Pain " of " international pharmacodynamics document " the 169th volume the 2nd phase 384-393 page or leaf, Arch.Int.Pharmacodyn., Vol.169, No.2 (1967) pp.384-393); Milne, G.M.﹠amp; " mutual relationship of plasma concentration that piroxicam to the analgesic property of animal body and with experiment record " (" the The Analgesic Properties of Piroxicam in Animalsand Correlation with Experimentally Determined Plasma Levels " of T.M.Twomey on " reagent and effect " the 10th volume the 1/2nd phase 31-37 page or leaf, Agents and Actions, Vol.10, No.1/2 (1980) .pp.31-37); Randall, L.O.﹠amp; " inflammation being organized the measuring method of analgesic activities " on " international pharmacodynamics document " the 111st volume the 4th phase 409-419 page or leaf of J.J.Selitto (A Methodfor Measurement of Analgesic Activity on Inflamed Tissue "; Arch.Int.Pharmacodyn.; Vol.111; No.4 (1957), pp.409-419); Winter, C.A.﹠amp; L.Faltaker is at " the nociception threshold value that influenced by proinflammatory agent and various anti-nociception medicine parenterai administration " (" Nociceptive Thresholds as Affected by ParenteralAdministration of and ofirritants Various Antinociceptive Drugs " of " pharmacology and experimental therapeutic magazine) " the 148th volume the 3rd phase 373-379 page or leaf, J.Pharmacol.Exp.Ther., Vol.148, No.3 (1965), pp.373-379), the disclosure of all these documents is all for referencial use in conjunction with people this paper.
Many anti-inflammatory drugs, particularly nonsteroid anti-inflammatory drugs (NSAID) can cause undesirable gastrointestinal side-effect, especially when oral; This side effect can comprise ulcer and erosion.These common asymptomatic side effect meetings become seriously to arrive to be needed to be in hospital, even can be fatal.Compare the common less this gastrointestinal side-effect that causes of compound of the present invention with other NSAID.Compounds more of the present invention even stomach provide protection is arranged, it can prevent gastroenteritic ulcer and erosion, particularly those ulcer and erosions that caused by ethanol or other NSAID.
Some NSAID can cause the undesirable increase of some liver enzyme level in whole body when the whole body administration.Compound of the present invention seldom causes usually or does not have a liver enzyme side effect.
Being used for compound of the present invention can prepare with following total reaction flow process:
Initial substituted benzene compound can carry out nitrated in sulfuric acid with nitric acid, then the nitro-compound that forms is catalysed and reduced into corresponding aniline.This aniline is to make the key intermediate with the urea that replaces in various degree.With isocyanic ester or the reaction of isothiocyanic acid ester, generate N, N ＇-dibasic urea or thiourea.Same aniline compound can react with phosgene or thio phosgene, generates corresponding isocyanic acid compound or isothiocyanic acid compound, and they generate N, N ＇, N ＇-trisubstituted urea or thiourea with the amine reaction again.Carry out the reductive amination reaction with aldehyde and aniline intermediate and generate substituted aniline, and then react, generate N, N ＇-dibasic urea or thiourea with isocyanic ester or isothiocyanic acid ester.
Nitrated benzene can be used zinc powder reduction, generates oxyamine, and then reacts with isocyanic ester or isothiocyanic acid ester, forms the urea or the thiourea of N-hydroxy-n ＇-replacement.
Synthetic embodiment
Following non-limiting example provides relevant target compound synthetic further data.
Embodiment 1
N-(the 7-tertiary butyl-2,3-dihydro-3,3-dimethyl-5-benzofuryl)-N ＇-methyl urea
The step 1:7-tertiary butyl-2,3-dihydro-3,3-dimethyl-5-nitrobenzofuran
At the 7-tertiary butyl-2,3-dihydro-3 in glacial acetic acid (80 milliliters) solution of 3-dimethyl benzofuran (10.0 grams, 49.0 mmoles), drips 70%HNO
3(4.0 milliliters, 5.7 grams, 63.7 mmoles).In the interpolation process, the reaction mixture deepening is deep green.With TLC (2% ethyl acetate/hexane) monitoring reaction, stirred 4 hours at 22 ℃ then.Then, reaction mixture is distributed between ether (100 milliliters) and water (2 * 100 milliliters).The ether layer washs with saturated aqueous sodium carbonate (50 milliliters), and dry (sal epsom) filters also evaporation, forms red solid (9.12 restrain).Carry out crystallization with hexane,, be orange prism (2.26 grams, 18.5%) to obtain title compound.After-crop obtains the lower material of purity (4.93 grams, 40.3%), its not purified just use, fusing point=93-94 ℃.
5-amino-7-the tertiary butyl-2,3-dihydro-3, the 3-dimethyl benzofuran:
With the 7-tertiary butyl-2,3-dihydro-3,3-dimethyl-5-nitrobenzofuran (2.2 gram, 8.8 mmoles) and 10% palladium charcoal (200 restrain), in dehydrated alcohol (60 milliliters), in 40psi hydrogen pressure and 22 ℃, hydrogenation is 3 hours in the Parr hydrogenation equipment.With TLC (hexane: ethyl acetate=19: 1; Use the Dragendorff reagent colour development) judge that reaction finishes.Reaction mixture upward filters at Celite (diatomite), and evaporation obtains title compound then, is red-purple solid (1.7 grams, 88%), its not purified just use.
Step 3:N-(the 7-tertiary butyl-2,3-dihydro-3,3-dimethyl-5-benzofuryl)-N ＇-methyl urea
Methyl isocyanate (0.14 milliliter, 2.28 mmoles) is dripped at 5-amino-7-tertiary butyl-2, and 3-dihydro-3 is in ether (5 milliliters) solution of 3-dimethyl benzofuran (500 milligrams, 2.28 mmoles).Formed solid, water after 1 hour (10 milliliters) termination reaction through 0.5 hour.Reaction solution extracts with ether (3 * 10 milliliters), and then with organic layer drying (sal epsom), and evaporation obtains tawny solid (550 milligrams).This solid carries out recrystallization with ethyl acetate and obtains product, is white prism (350 milligrams, 56%) that fusing point is 193-194 ℃.
Embodiment 2
N-(the 7-tertiary butyl-2,3-dihydro-3,3-dimethyl-5-benzofuryl)-N ＇-ethyl carbamide
Ethyl isocyanate (0.18 milliliter, 2.28 mmoles) is dripped at 5-amino-7-tertiary butyl-2, and 3-dihydro-3 is in ether (5 milliliters) solution of 3-dimethyl benzofuran (500 milligrams, 2.28 mmoles).After 10 minutes, formed solid, water after 40 minutes (10 milliliters) termination reaction.Reaction solution extracts with ether (3 * 10 milliliters), and then with organic layer drying (sal epsom), and evaporation obtains tawny solid (657 milligrams).This solid carries out recrystallization with ethyl acetate and obtains title compound, is white prism (335 milligrams, 51%) that fusing point is 197-198 ℃.
Embodiment 3
N-(the 7-tertiary butyl-2,3-dihydro-3,3-dimethyl-5-benzofuryl)-N ＇-propyl group urea
Propyl isocyanate (0.21 milliliter, 2.28 mmoles) is dripped in ether (5 milliliters) solution of (the 7-tertiary butyl-2,3-dihydro-3,3-dimethyl-5-cumarone)-amine (500 milligrams, 2.28 mmoles).After 10 minutes, formed solid, water after 40 minutes (10 milliliters) termination reaction.Reaction solution extracts with ether (3 * 10 milliliters), then organic layer is carried out drying (sal epsom), and evaporation obtains beige solid (650 milligrams).This solid carries out recrystallization with ethyl acetate and obtains white solid (270 milligrams, 39%), and fusing point is 193-194 ℃.
Embodiment 4
N-(the 7-tertiary butyl-2,3-dihydro-3,3-dimethyl-5-benzothienyl)-N ＇-methyl urea
Step 1:2-bromo-6-t-butylthio phenol.At 23 ℃,, add n-Butyl Lithium (198.4 mmoles, 99.2 milliliters lentamente to the solution of tetramethylenediamine (198.4 mmoles, 30 milliliters) in hexanaphthene (140 milliliters); 2M solution in hexanaphthene).The solution that obtains is cooled to 0 ℃.With the solution of 2-t-butylthio phenol (15.0 grams, 90.2 mmoles) in hexanaphthene (40 milliliters), temperature is remained on below 10 ℃ then with the certain speed adding.Then reaction solution was stirred 5 hours at 0 ℃, then be warming up to 23 ℃ and spend the night.In 23 ℃, in the yellow solution that forms, added s-butyl lithium (90.2 mmoles, 69.4 milliliters of 1.3M solution in hexanaphthene) through 0.5 hour.The solution that forms gradually becomes orange.1.5 after hour, through 1 hour orange muddy reaction mixture is led people 1 in stirring down, 2-dibromotetrafluoroethane (180.4 mmoles, 21.5 milliliters) is in the solution of THF (50 milliliters).After adding end, use the reaction mixture of 1N HCl (80 milliliters) cancellation gained, and extract with hexane (3 * 100 milliliters).Hexane is carried out drying (sal epsom) and evaporation, obtain dark-coloured oily matter (29.49 gram).This oily matter is poured in the 1N sodium hydroxide (100 milliliters), extracted with methylene dichloride (3 * 50 milliliters).Discard organic phase,, use methylene dichloride (3 * 100 milliliters) extraction again with 12N hcl acidifying water.With organic phase drying (sal epsom) and evaporation, obtain title compound, be yellow oil.
Step 2:2-bromo-6-tert-butyl-phenyl 2-methylallyl thioether.With 2-bromo-6-t-butylthio phenol (12.4 grams, 50.6 salt of wormwood (8.44 grams mmole),, 61.1 mmole), NaI (766 milligrams, 50.6 mmoles) and the solution reflux of β-methylallyl chloride (5.17 milliliters, 50.6 mmoles) in acetone (250 milliliters) are 2 hours.With TLC (hexane) monitoring reaction.Allow reaction mixture be cooled to 23 ℃, elimination precipitated solid then.Evaporated filtrate obtains dark yellow oily thing, and it is poured in the hexane (100 milliliters), stirs 20 minutes with silica gel (10 gram).Elimination silica gel also discards, and evaporated filtrate obtains title compound, is faint yellow oily thing.
The step 3:7-tertiary butyl-2,3-dihydro-3,3-dimethyl-5-oil of mirbane thiophthene
With (2-bromo-6-tert-butyl-phenyl)-(2-methylallyl)-thioether (9.00 grams, 30.0 mmole), two-sec.-propyl ethylamine is (160 milliliters, 0.90 mole) and 80% Hypophosporous Acid, 50 (58 grams, 0.90 the solution in mole) Zai diox (450 milliliters) froths and deoxygenation 0.5 hour by nitrogen.This solution of reflux, with 0.5 hour be the interval, each 0.5 milliliter of ground adds diox (5 milliliters) solution of the azo-two-isobutyl acyl cyanide (1.7 gram, 8.8 mmoles) of same deoxygenation with syringe.With TLC (hexane) monitoring reaction.After 24 hours, allow reaction mixture be cooled to 23 ℃, and distribute with 1N hydrochloric acid (300 milliliters), salt solution (100 milliliters) and ether (3 * 150 milliliters).Ether extract after the merging with 1N sodium hydroxide (3 * 50 milliliters) and water (2 * 50ml) strip, dry (sal epsom) then, evaporation obtains crude product, is yellow oil.To this material carry out short-path vacuum distillation (85 ℃, 40mmHg), obtain title compound, be light yellow oil.
The step 4:7-tertiary butyl-2,3-dihydro-3,3-dimethyl 5-nitro-thionaphthene.At the 7-tertiary butyl-2,3-dihydro-3 in glacial acetic acid (30 milliliters) solution of 3-dimethyldibenzothiophene (4.0 grams, 18.2 mmoles), drips 70%HNO
3(2.0 milliliters, 2.8 grams, 31.8 mmoles).In the interpolation process, the reaction mixture deepening is deep green.With TLC (2% ethyl acetate/hexane) monitoring reaction, then reaction mixture is distributed between ether (50 milliliters) and water (2 * 50 milliliters).The ether layer washs with saturated aqueous sodium carbonate (50 milliliters), and dry (sal epsom) filters also evaporation, forms red solid.Carry out crystallization with hexane, obtain title compound, be orange prism.After-crop obtains the lower material of purity.With itself and last time merging, not purifiedly just use.
The step 5:5-amino-7-tertiary butyl-2,3-dihydro-3,3-dimethyl benzofuran.
With the 7-tertiary butyl-2,3-dihydro-3, the suspension of 3-dimethyl-5-oil of mirbane thiophthene (2.6 gram, 8.8 mmoles) in dehydrated alcohol (60 milliliters), in 40psi hydrogen pressure and 22 ℃, hydrogenation is 3 hours in the Parr hydrogenation equipment.With TLC (hexane: ethyl acetate=19: 1; Use the Dragendorff reagent colour development) judge that reaction finishes.Reaction mixture is gone up at Celite (diatomite) and is filtered, and evaporation obtains title compound then, is the red-purple solid, its not purified just use.
Step 6:N-(the 7-tertiary butyl-2,3-dihydro-3,3-dimethyl-5-benzothienyl)-N ＇-methyl urea
Methyl isocyanate (0.14 milliliter, 2.28 mmoles) is dripped at 5-amino-7-tertiary butyl-2, and 3-dihydro-3 is in ether (5 milliliters) solution of 3-dimethyldibenzothiophene (550 milligrams, 2.33 mmoles).Formed solid gradually, water (10 milliliters) termination reaction.Reaction solution is extracted with ether (3 * 10 milliliters), then organic layer is carried out drying (sal epsom), and evaporation obtains the tawny solid.This solid carries out recrystallization with ethyl acetate and obtains product, is white prism, fusing point＞150 ℃.
Composition
The present composition comprises the The compounds of this invention and the pharmaceutically acceptable carrier of safe and effective amount." safe and effective amount " refers in this article, and within rational medical assessment scope, the amount of compound is enough to obviously improve the state of an illness of being treated, but is not enough to cause severe side effect (rational curative effect/risk ratio is arranged).The safe and effective amount of compound all multifactor and different according in age of the concrete state of an illness of receiving treatment, the patient that receives treatment and physical condition, the severity of the state of an illness, the time length of treatment and the treatment situation of depositing, the concrete doctor's knowledge and skills scopes such as pharmaceutically acceptable carrier used.
The present composition should comprise about 0.1wt% (weight percent) to about 99.9wt% compound, and about 20% to about 80% is better, and preferably about 40% to about 70%.
Except that compound, the present composition also comprises pharmaceutically acceptable carrier." pharmaceutically acceptable carrier " refers to one or more consistency solids or liquid filler thinner in this article or becomes capsule material, and they are fit to use to people or more rudimentary animal." consistency " refers to that at this each component can be admixed each other mutually with The compounds of this invention and their in composition, and the interaction of composition drug effect does not take place obviously to reduce under general service condition the mode of this blending.Certainly, be fit to use to people or more rudimentary animal in order to make them, pharmaceutically acceptable carrier must have sufficiently high purity and enough low toxicity.
Can sugar be arranged as the part example of pharmaceutically acceptable carrier, for example lactose, dextrose plus saccharose; Starch, for example W-Gum and yam starch; Mierocrystalline cellulose and derivative thereof, for example Xylo-Mucine, ethyl cellulose, cellulose ethanoate; Powdered tragacanth; Fructus Hordei Germinatus; Gelatin; Talcum; Solid lubricant, for example stearic acid, Magnesium Stearate; Calcium sulfate; Vegetables oil, for example peanut oil, Oleum Gossypii semen, sesame oil, sweet oil, Semen Maydis oil, theobroma oil; Polyvalent alcohol, for example propylene glycol, glycerine, sorbyl alcohol, N.F,USP MANNITOL and polyoxyethylene glycol; Alginic acid; Emulsifying agent, for example tween
Wetting agent, for example sodium lauryl sulphate; Tinting material; Seasonings; Vehicle; The film-making agent; Stablizer; Antioxidant; Sanitas; Apirogen water; Isotonic saline solution and phosphate buffered saline buffer.
The pharmaceutically acceptable carrier that selection and The compounds of this invention share depends primarily on the medication of compound.
If The compounds of this invention is used for injection, should adopt the non-vein injection; Pharmaceutically acceptable preferably carrier be contain can with the stroke-physiological saline solution of the suspension agent of blood compatibility, its pH is transferred to about 7.4.This Injectable composition should comprise about 1% to about 50% The compounds of this invention, and about 5% to about 25% is better, and in addition, every dose of about 10mg is also better to about 600mg The compounds of this invention.
Being fit to the local pharmaceutically acceptable carrier that uses comprises and is applicable in lotion, creme, the gelifying agent etc. those.The local composition that uses should comprise about 1% to about 50% softener, and about 5% to about 25% is better.This local composition that uses should comprise about 0.1% to about 50% The compounds of this invention, and about 0.5% to about 10% is better, and in addition, every dose of about 5mg is also better to about 3500mg The compounds of this invention.
Use The compounds of this invention mode preferably is oral.So unit dosage is tablet, capsule and so on preferably, wherein comprise the compound of safe and effective amount, this amount is advisable to about 3500mg with about 5mg, and about 10mg is better to about 1000mg, and preferably about 25mg is to about 600mg.The pharmaceutically acceptable carrier that is fit to the preparation oral unit dosage form is well known in the art.Less important Consideration such as taste, cost and preservation period nonessential concerning the object of the invention is depended in selecting for use of they, and persons skilled in the art can easily make one's options.
Many in the The compounds of this invention is hydrophobic.If a kind of aqueous composition is provided or dissolves in the water-based medium or miscible with it composition, can comprise solubilizing agent in the composition.The non-limitation example of this class solubilizing agent comprises polyoxyethylene glycol, propylene glycol, ethanol and polyoxyethylene (35) Viscotrol C.
The good especially oral compositions that is applicable to the present composition is disclosed in the United States Patent (USP) 5 that the name of authorizing Kelm and Bruns on February 23rd, 1993 is called " Tebufelone pharmaceutical composition " with carrier, 189, the name of authorizing Kelm and Dobrozsi on January 25th, 066 and 1994 is called the United States Patent (USP) 5 of " Tebufelone solid dispersed system: compositions ", in 281,420.
Method
The present invention's content on the other hand is that to treat or prevent with the inflammation by the The compounds of this invention that people or more rudimentary animal to needs treatments give safe and effective amount be the method for the disease of feature." is the disease of feature with the inflammation " refers to known those illnesss that are associated with inflammation at this, can comprise the illness of sacroiliitis and so on (for example rheumatoid arthritis, osteoarthritis, arthritis psoriasis, teenager's property sacroiliitis, Josef Reiter (Reiter) syndrome, infective arthritis and ankylosing spondylitis, systemic lupus erythematosus, erythema and gout) for example and with the generation of the disease-related connection that can make a definite diagnosis or unconnected inflammation.The disease that with the inflammation is feature also comprises oral inflammation (for example inflammation that is associated with gingivitis or periodontopathy); Gastrointestinal tract inflammation (for example inflammation that is associated with ulcer and irritable bowel syndrome); The disease that is associated with tetter (for example psoriasis, acne and other skin inflammation); Respiratory inflammation (for example asthma, bronchitis and allergic disease); Inflammation of the central nervous system (for example Alzheimer (Alzheimer) disease).
The present invention's content on the other hand is to treat or the method for prevent irritation by the The compounds of this invention that people or more rudimentary animal to needs treatments give safe and effective amount.Can The compounds of this invention be treated or the pain of preventing comprises tip pain, dysmenorrhoea, toothache and Dorsal root pain by taking.
The present invention's content on the other hand is the method for the treatment of or preventing oxidative damage by the The compounds of this invention that people or more rudimentary animal to the needs treatment give safe and effective amount.Though concrete mechanism is not only a kind of, it is believed that The compounds of this invention suppresses the synthetic of leukotriene, thereby can reduce neutrophil gathering in the inflammation position.
The present invention's content on the other hand is to treat or prevent stomach or duodenal ulcer or rotten to the corn method by the The compounds of this invention that people or more rudimentary animal to the needs treatment give safe and effective amount.Specifically, can treat and/or prevent this class ulcer or the erosion that causes because of ethanol or non-steroid antiphlogiston by giving preferred The compounds of this invention.
It is known in the field measuring the gi tract security of The compounds of this invention or the correlation method of stomach protectiveness or stomach healing property.
In following reference, disclose and/or mentioned the method for measuring acute gi tract security: Unangst, P.C., G.P.Shrum, D.T.Connor, R.D.Dyer and D.J.Schrier, " as the l of the novelty of 5-lipoxygenase and cyclooxygenase double inhibitor, 2; 4-oxadiazole and 1; 2,4-thiadiazoles ", journal of medicinal chemistry (J.Med.Chem.), 35 volumes (1992), pp.3691-3698; Segawa; Y.O.Ohya; T.Abe; T.Omata etc.; " new antiphlogiston 1-(right-chlorobenzene formacyl)-5-methoxyl group-2-methyl-3-indoleacetic acid N-{3-[3-(piperidino methyl) phenoxy group] propyl group }-the carbamyl methylthiol } anti-inflammatory, analgesia and refrigeration function and the gastrointestinal toxicity thereof of ethyl ester "; Arzneim.-Forsch./Drug Res., 42 volumes (1992), pp.954-992.In the method that this paper discloses, be typically the stomach of after administration, checking animal in 2 hours.Following reference discloses and/or has mentioned the method for measuring subacute gastrointestinal toxicity: Melarange, R., C.Gentry etc., " Nabumetone or its active metabolite; the anti-inflammatory and the gi tract effect of 6-methoxyl group-2-naphthyl acetic acid (6MNA) " Dig.Dis.Sci., 37 volumes (1992), PP.1847-1852; Wong, S., S.J.Lee etc., " BF-389-be difficult for for one kind causing the anti-inflammatory agent of the novelty of ulcer-the arthritis characteristic " Agents Actions, 37 volumes (1992), pp.90-91.
In following reference, disclose and/or mentioned the method for measuring acute stomach protection: Playford; R.J.; D.A.Versey; S.Haldane; M.R.Alison and J.Calan, " fragrant its Buddhist nun is to the dose-dependently effect (Dose-dependent Effects of Fentanyl on Indometharin-inducedGastric Damage) of gastric damage due to the INDOMETHACIN " digestion (Digestion) 49 volume (1991) pp.198-203.In the method that this paper discloses,, give female Lewis rat (130-175 gram) oral with The compounds of this invention (40 mg/kg, a day twice) or vehicle preceding 2 hours of the INDOMETHACIN that gives gastric injury dosage and before just giving INDOMETHACIN.Use CO after 4 hours
2Suffocate and put to death rat.Measure the damage (millimeter of hemorrhage damage) of body of stomach by digital picture.
The preferred administering mode of The compounds of this invention is oral, but other known medication is as also being feasible through mucocutaneous (as through skin, rectum etc.) and parenteral route (as by subcutaneous injection, intramuscularly, intra-arterial injection, intravenous injection etc.).Also comprise ophthalmic administration and inhalation.Like this, that concrete administering mode includes, but not limited to is oral, transdermal, in mucous membrane, hypogloeeis, nose, intramuscular, intravenously, intraperitoneal, subcutaneous administration and topical.
The compounds of this invention preferred dosage scope is more preferably about 0.5mg/kg to about 12mg/kg for about 0.2mg/kg arrives about 70mg/kg.Preferred injected dose comprises that about 0.1mg/kg is to about 10mg/kg The compounds of this invention.Preferred topical dosage comprises about 1mg/cm
2To about 200mg/cm
2Be applied to the The compounds of this invention of skin surface.Preferred oral dosage comprises about 0.5mg/kg to about 50mg/kg, is more preferably about 1mg/kg to about 20mg/kg, and best is that about 2mg/kg is to about 10mg/kg The compounds of this invention.Such dosage approximately once is advisable to about six times with the every day administration, is more preferably administration every day about twice to about four times.The dosage of this administration every day was at least two weeks to be advisable in one week of administration at least preferably, was more preferably at least one month, more preferably at least 2 months, and preferably at least 6 months, 1 year, 2 years or longer time.
The embodiment of composition and method
Following non-limiting example has illustrated the present invention.
Embodiment A
By ordinary method,, prepare the pharmaceutical composition that is tablet form by following prescription as mixing and directly punching press:
Component consumption (milligram/sheet)
Compound 1 200
Microcrystalline Cellulose 100
Sodium starch glycolate 30
Magnesium Stearate 3
When every day during twice oral pharmaceutical, top composition has obviously reduced the inflammation of suffering from the rheumatoid arthritis people.Take said composition twice and also obtained obvious effects patient every day of give suffering from osteoarthritis.
Embodiment B
By the method for routine, be the pharmaceutical composition of capsule form by following formulation:
Amounts of components (milligram/capsule)
Compound 2 200
Lactose fills up the capsule volume
Oral once a day above-mentioned pharmaceutical capsules can obviously alleviate the symptom of suffering from rheumatoid arthritis or osteoarthritis patient.
Embodiment C
By the method for routine, be the pharmaceutical composition of liquid form by following formulation:
Amounts of components
3 200 milligrams of compounds
4 milliliters of EtOH
0.4 milligram of methylcellulose gum
76 milliliters of distilled water
1.6 milliliters of tween 80s
Oral once a day 50 milliliters of said medicine obviously alleviate the symptom of suffering from rheumatoid arthritis or osteoarthritis patient.
Embodiment D
By the method for routine, press the pharmaceutical composition of following formulation liquid form:
Amounts of components
1 200 milligrams of the compounds of crystallite (micritization)
50 milligrams of Avicel (Microcrystalline Cellulose)
1.6 milliliters of tween 80s
0.4 milligram of methylcellulose gum
80 milliliters of deionized waters
Oral once a day 50 milliliters of said medicine obviously alleviate the patient's who suffers from rheumatoid arthritis or osteoarthritis symptom.
Though the present invention has disclosed specific technical scheme, for a person skilled in the art, can make variations and modifications and not deviate from the spirit and scope of the present invention the composition that this paper discloses.Appending claims covers all such modifications in the scope of the invention.
Claims (17)
1. the compound that has following structure:
In the formula,
(a) n is 1-3;
(b) X is selected from: O, S, SO or SO
2
(c) Y is hydrogen independently of one another, or the straight-chain alkyl of 1-4 carbon atom, branched hydrocarbyl or cyclic hydrocarbon radical, and perhaps Y is together with each other and forms the alkane ring of 3-7 atom;
(d) Z is a hydrogen, or the straight-chain alkyl of 3-10 non-hydrogen atom, branched hydrocarbyl or cyclic hydrocarbon radical;
(e) W is O or S; And
(f) R
1, R
2And R
3Be hydrogen independently of one another, the straight-chain alkyl of 1-10 carbon atom, branched hydrocarbyl or cyclic hydrocarbon radical, aryl, heterocyclic radical, heteroaryl, hydroxyl or alkoxyl group; Perhaps R
1, R
2And R
3Can mutually combine forms one or more rings, and each ring has 3-7 atom and 1-3 atom wherein arranged can be heteroatoms.
2. compound as claimed in claim 1 is characterized in that, X is oxygen or sulphur, R
1And R
2Be hydrogen or methyl.
3. compound as claimed in claim 1 is characterized in that each Y is independently selected from hydrogen, methyl and ethyl; Z is selected from the C of two side chains
4-C
6Branched alkane alkyl and unsubstituted C
3-C
6Cycloalkyl group.
4. compound as claimed in claim 3 is characterized in that X is an oxygen, and two Y are methyl, and Z is the tertiary butyl.
5. compound as claimed in claim 4 is characterized in that R
3Be saturated or the C of two keys is arranged between non-terminal carbon
1-C
6Straight-chain alkyl or monobranched hydrocarbons base or have the straight-chain alkyl of end-rings alkyl, perhaps C
3-C
6Cycloalkyl group.
6. compound as claimed in claim 5 is characterized in that X is an oxygen, and R
1And R
2Be hydrogen.
7. compound as claimed in claim 6 is characterized in that n is 1.
8. compound as claimed in claim 7 is characterized in that R
3Be selected from following group: methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, 1-methyl-propyl, 2-methyl-propyl, 1-methyl butyl, oxyethyl group, benzyl, styroyl, cyclobutyl, cyclopentyl and cyclohexyl.
9. compound as claimed in claim 8 is characterized in that W is an oxygen.
10. compound as claimed in claim 9 is characterized in that R
3Be selected from following group: methyl, ethyl, n-propyl, normal-butyl and oxyethyl group.
11. compound as claimed in claim 10 is characterized in that, R
3Be methyl, ethyl or propyl group.
12. a composition is characterized in that, it comprises described compound of claim 1 and pharmaceutically acceptable carrier.
13. a method for the treatment of inflammation or pain is characterized in that, comprises to the people of this treatment of needs or the described compound of claim 1 of more rudimentary animal significant quantity safe in utilization.
14. the method for a treatment of arthritis is characterized in that, comprises the described compound of claim 1 to the oral about 1-20 milligram people's every day/kilogram of this treatment of needs.
15. a composition is characterized in that, it comprises described compound of claim 11 and pharmaceutically acceptable carrier.
16. a method for the treatment of inflammation or pain is characterized in that, it comprises the described compound of claim 11 to the people of this treatment of needs or more rudimentary animal significant quantity safe in utilization.
17. the method for a treatment of arthritis is characterized in that, it comprises the described compound of claim 11 to the oral about 1-20 milligram people's every day/kilogram of this treatment of needs.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/595,158 | 1996-02-01 | ||
| US08/595,158 US5684041A (en) | 1996-02-01 | 1996-02-01 | Dihydrobenzofuran and related compounds useful as anti-inflammatory agents |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1210529A true CN1210529A (en) | 1999-03-10 |
| CN1097588C CN1097588C (en) | 2003-01-01 |
Family
ID=24381988
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|---|---|---|---|
| CN97191977A Expired - Fee Related CN1097588C (en) | 1996-02-01 | 1997-01-30 | Dihydrobenzofuran and related compounds useful as anti-inflammatory agents |
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| Country | Link |
|---|---|
| US (1) | US5684041A (en) |
| EP (1) | EP0879231B1 (en) |
| JP (1) | JP3095421B2 (en) |
| KR (1) | KR100350920B1 (en) |
| CN (1) | CN1097588C (en) |
| AT (1) | ATE277031T1 (en) |
| AU (1) | AU730319B2 (en) |
| BR (1) | BR9707250A (en) |
| CA (1) | CA2244194C (en) |
| DE (1) | DE69730817T2 (en) |
| DK (1) | DK0879231T3 (en) |
| ES (1) | ES2229331T3 (en) |
| MX (1) | MX9806251A (en) |
| NO (1) | NO983525L (en) |
| NZ (1) | NZ331618A (en) |
| WO (1) | WO1997028143A1 (en) |
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| US7435837B2 (en) * | 2003-10-24 | 2008-10-14 | Wyeth | Dihydrobenzofuranyl alkanamine derivatives and methods for using same |
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| DK2398500T3 (en) | 2009-02-20 | 2019-05-13 | 2 Bbb Medicines B V | GLUTATHION-BASED PHARMACEUTICAL DELIVERY SYSTEM |
| AU2010245823B2 (en) | 2009-05-06 | 2016-11-24 | Laboratory Skin Care, Inc. | Dermal delivery compositions comprising active agent-calcium phosphate particle complexes and methods of using the same |
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- 1996-02-01 US US08/595,158 patent/US5684041A/en not_active Expired - Fee Related
-
1997
- 1997-01-30 JP JP09527757A patent/JP3095421B2/en not_active Expired - Fee Related
- 1997-01-30 AT AT97904014T patent/ATE277031T1/en not_active IP Right Cessation
- 1997-01-30 AU AU18428/97A patent/AU730319B2/en not_active Ceased
- 1997-01-30 CN CN97191977A patent/CN1097588C/en not_active Expired - Fee Related
- 1997-01-30 DK DK97904014T patent/DK0879231T3/en active
- 1997-01-30 DE DE69730817T patent/DE69730817T2/en not_active Expired - Fee Related
- 1997-01-30 CA CA002244194A patent/CA2244194C/en not_active Expired - Fee Related
- 1997-01-30 KR KR1019980705951A patent/KR100350920B1/en not_active IP Right Cessation
- 1997-01-30 ES ES97904014T patent/ES2229331T3/en not_active Expired - Lifetime
- 1997-01-30 EP EP97904014A patent/EP0879231B1/en not_active Expired - Lifetime
- 1997-01-30 BR BR9707250A patent/BR9707250A/en not_active Application Discontinuation
- 1997-01-30 NZ NZ331618A patent/NZ331618A/en unknown
- 1997-01-30 WO PCT/US1997/001308 patent/WO1997028143A1/en active IP Right Grant
-
1998
- 1998-07-31 NO NO983525A patent/NO983525L/en not_active Application Discontinuation
- 1998-08-03 MX MX9806251A patent/MX9806251A/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| NO983525L (en) | 1998-09-30 |
| KR100350920B1 (en) | 2002-11-18 |
| US5684041A (en) | 1997-11-04 |
| EP0879231B1 (en) | 2004-09-22 |
| JP3095421B2 (en) | 2000-10-03 |
| KR19990082223A (en) | 1999-11-25 |
| DK0879231T3 (en) | 2004-12-20 |
| WO1997028143A1 (en) | 1997-08-07 |
| NZ331618A (en) | 2000-08-25 |
| MX9806251A (en) | 1998-11-30 |
| JPH11503467A (en) | 1999-03-26 |
| AU730319B2 (en) | 2001-03-01 |
| CA2244194C (en) | 2003-05-06 |
| DE69730817T2 (en) | 2005-02-03 |
| AU1842897A (en) | 1997-08-22 |
| BR9707250A (en) | 1999-04-06 |
| NO983525D0 (en) | 1998-07-31 |
| EP0879231A1 (en) | 1998-11-25 |
| CN1097588C (en) | 2003-01-01 |
| ES2229331T3 (en) | 2005-04-16 |
| ATE277031T1 (en) | 2004-10-15 |
| DE69730817D1 (en) | 2004-10-28 |
| CA2244194A1 (en) | 1997-08-07 |
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